1. Field of the Invention
The present invention generally relates to biodegradable polymer compositions, in particular those containing both phosphoester linkages in the polymer backbone and chargeable groups linked to the backbone through a phosphoester bond. These biodegradable polymers of the invention are designed for the controlled release of drugs and genes, particularly as carriers for gene therapy and for the delivery of protein drugs. The invention also has wide applicability in tissue engineering applications, where the sustained delivery of growth factors is achieved through gene transfer.
2. Background
Polymeric controlled drug delivery has significantly improved the success of many drug therapies (Langer, 1990, New methods of drug delivery, Science 249: 1527-33; Poznansky, et al., 1984, Biological approaches to the controlled delivery of drugs: a critical review, Pharmacol. Rev. 36: 277-336). In such a delivery system, pharmacokinetics and biodistribution of the drug depend upon the physiochemical properties and/or degradation properties of the polymer carriers. In general, polymeric carriers offer advantages over other delivery systems: polymeric systems potentially have more controllable release kinetics, better stability in storage, and have better biocompatibility. A biodegradable drug-carrier could offer features difficult to attain from non-biodegradable systems. Other than obviating the need to remove the drug-depleted devices, a biodegradable system is also applicable to a wider range of drugs. More and more new polymer carriers have been proposed for controlled drug delivery, although poly(lactide-co-glycolide) copolymers still dominate the field. There is clearly justification to continue to develop new biodegradable drug-carriers, because of the increasing need in the emerging new applications. The widening scope of applications requires polymeric carriers to assume different configurations and serve additional functions other than just passive delivery. For instance, applying the controlled release device as more than just a monolithic matrix, for example, as a coating material for a drug-eluting stent, may obligate the polymer to have elastomeric properties. In the new and exciting field of tissue engineering where local and sustained delivery of growth factors and/or genes encoding these growth factors may influence the course of tissue development, the drug-carrier may also need to perform a double-duty to provide structural support or scaffolding functions. To achieve active targeting, it would involve conjugation of ligands to the polymeric carriers, which requires the polymeric carrier to contain functional groups for derivatization. In the field of gene delivery, polymeric gene carriers need to be of polycationic nature and should have the structural flexibility to include targeting feature and parameters affecting the intracellular trafficking of the genes (Han, et al., 2000, Development of biomaterials for gene therapy, Molecular Therapy 2: 302-317; Varga, et al., 2000, Receptor-mediated targeting of gene delivery vectors: insights from molecular mechanisms for improved vehicle design. Biotechnol. Bioeng. 70: 593-605). With such a broad utility for these biodegradable drug-carriers, no one single material can be expected to satisfy all requirements of different applications.
Gene therapy has been progressively developed with the hope that it will be an integral part of medical modalities in the future. Gene delivery system is one of the key components in gene medicine, which directs the gene expression plasmids to the specific locations within the body. The control of gene expression is achieved by influencing the distribution and stability of plasmids in vivo and the access of the plasmids to the target cells, and affecting the intracellular trafficking steps of the plasmids (Mahato, et al., 1999, Pharmaceutical perspectives of nonviral gene therapy, Adv. Genet. 41: 95-156). Recently, there is an increasing interest in developing systems for sustained release of DNA. Such a system could be used to achieve localized and enhanced gene expression in skeletal muscle. It would find wide applications in treating muscle and nerve disorders, providing systemic circulation of secretory proteins, and as a genetic vaccine carrier. Encapsulation of DNA in PLGA nanoparticles (Cohen, et al., 2000, Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Therapy 7: 1896-1905) and absorption of plasmid to the surface of cationic PLGA microparticles (Singh, et al., 2000, Characterization of cationic microparticles with adsorbed plasmid DNA. Proceed. Int'l. Symp. Control. Rel. Bioact. Mater., 27, 6405-6406) have been reported recently to achieve sustained release of plasmid DNA. Sustained release of DNA was observed for 2 to 4 weeks in these systems. The cationic microparticles induced about four-fold higher gene expression level in muscle at day 14, and induced higher Th1 and Th2 responses in mice (Singh, et al., 2000, Cationic microparticles: A potent delivery system for DNA vaccines. Proc. Natl. Acad. Sci. USA 97(2): 811-816). However, both systems are limited by the low DNA loading levels (<1%) and the little room for optimization of DNA release kinetics. Other systems currently under investigations are non-biodegradable polymeric systems, e.g. poly(ethylene-co-vinyl acetate) (Luo, et al., 1999, Controlled DNA delivery systems. Pharm. Res. 16(8): 1300-1308) and Poloxamers (Lemieux, et al., 2000, A combination of poloxamers increases gene expression of plasmid DNA in skeletal muscle. Gene Therapy 7: 986-991). The present patent features a novel gene delivery system that based on the biodegradation of polymeric carriers to achieve a sustained release of plasmid DNA in a controlled manner.